Janus kinase (hereinafter, also referred to as “JAK”) performs some of the various functions of tyrosine kinases on cytoplasmic protein. A series of various functions of the JAK are carried out through the action of signal transducers and activators of transcription (“STAT”), and are important as a trigger of the cellular signalling system initiated by cytokines.
JAK is widely involved across the overall mechanism of cytokine expression initiation. Four JAK proteins (JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)) and 7 STAT molecules are known initiation factors. In particular, JAK family proteins play important roles in intrinsic and adaptive immune systems. It has been found that in the pathogenesis of rheumatoid arthritis, cytokine receptors containing the common gamma-chain are related to the expression of JAK1 and JAK3 proteins. It has also been found that the expression of a large number of cytokines and hormones are involved in the cytoplasmic signalling system. Pathologically, these facts suggest the likelihood of reduction in the expression of pathogenesis-related cytokines by inhibition of JAK1 and JAK3. Accordingly, compounds that may inhibit JAK proteins such as JAK1 and JAK3 may be useful in the treatment of multiple allergic diseases, inflammation and autoimmune diseases, including rheumatoid arthritis, lupus erythematosus, pauciarticular juvenile rheumatoid arthritis, arthritis, asthma, chronic obstructive pulmonary disease (COPD), tissue fibrosis (for example, myelofibrosis), eosinophilic leukocytosis inflammation, esophagitis, inflammatory bowel disease, organ transplant rejection, graft-versus-host disease, psoriasis, myositis, and multiple sclerosis.
Rheumatoid arthritis is a progressive autoimmune disease that causes intraarticular inflammation, pain, and injury. Inflammatory precursor cytokines (for example, tumor necrosis factors) are secreted by the action of T lymphocytes and B lymphocytes, and JAK (JAK1 and JAK3) relays the action of STAT from the inflammatory precursor cytokines and induces secretion of intracellular cytokines, causing joint inflammation and injury. Of a number of cytokines, IL-1, IL-6, and IL-16 are related to the growth of cells which mediate immune inflammatory responses, and also are likely closely related to the onset of rheumatoid arthritis. Many studies conducted on humans and animals have also revealed that gene expression through the JAK-STAT mechanism plays a significant role in inflammatory response control.
Vandeghinste et al. (WO 2005/124342) discovered that inhibition of JAK1 is a target mechanism useful for the treatment of various diseases, including osteoarthritis. According to an experimental result, JAK1-knockout mice died within 24 hours after birth due to immaturity of lymphocytes, since JAK1 plays an absolutely essential role in the development and maturation of lymphocytes. In JAK1-negative cells, due to non-functioning of type II cytokine receptors, the gamma-c subunit did not function, and consequently, related cytokine receptors, i.e., receptors using the gp130 subunit, did not function.
Among JAK family proteins, JAK2 is particularly related to myeloproliferative disorders. That is, inhibition of JAK2 may likely be helpful in the treatment of myeloproliferative disorders. JAK1, JAK2, and JAK3 proteins are all related to cancer, and were found to be useful for the treatment of tumors, and in particular, myelogenous leukemia (for example, acute myelogenous leukemia (AML)), and lymphoblastic leukemia (for example, acute lymphoblastic leukemia (ALL)).
In rheumatoid arthritis, from the understanding that inflammatory arthritis symptoms may be relieved by inhibiting the expression of STAT1, STAT3, STAT4, and STAT6 in the JAK-STAT signal transduction pathway, inhibition of the JAK-STAT signalling pathway by inhibiting the generation of inflammatory cytokines (for example, TNF-α, IL-1, and IL-6) which may increase manifestation of symptoms was found to be ideal. Targeting multiple signal transduction pathways is effective to inhibit pathological disease symptoms of rheumatoid arthritis.
A perfect therapy for rheumatoid arthritis has not yet been developed, and studies on related mechanisms are ongoing. In the pathogenesis of rheumatoid arthritis, multiple factors related to other immune and inflammatory diseases are involved. For this reason, if a drug for rheumatoid arthritis is developed, the drug may more likely be applicable in other immune and inflammatory diseases (for example, proliferative disease, graft-versus-transplant rejection, cartilage proliferative disorder, dysplasia, and IL-6 and interferon hypersecretion-related diseases). Therefore, through the present invention, it is possible to synthesize, produce, and formulate a material applicable to such diseases and symptoms as described above, and thus develop mass-producible medicines.